Functional role of extracellular vesicles and lipoproteins in the tumour microenvironment

Abstract

Cancer can be regarded as an invasive organ that exhibits unique plasticity provided by coordinated, cancer cell-stromal cell communication in the tumour microenvironment. Typical stress factors in the tumour niche, such as hypoxia and acidosis, are major drivers and modulators of these events. Recent findings reveal an important role of extracellular vesicles and lipoproteins in cancer cell adaption to exogenous stress. Adaptive mechanisms include stimulation of angiogenesis and increased metastasis. Here, we will discuss the similarities and distinct features of these endogenous nanoparticles and their roles as signalosomes and nutrient sources in cancer. We will focus on the accumulating evidence for a central role of cell-surface heparan sulphate proteoglycans in the uptake of extracellular vesicles and lipoproteins.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.

Keywords: exosomes; hypoxia; lipoproteins; microvesicles; proteoglycans.

Figure 1.

Distribution of lipoproteins versus EVs according to density gradient isolation (left scale) [17,18] and particle size (right scale). The relative size of lipoproteins is shown.

Figure 2.

Exosome-like EV uptake in U87-MG glioma cells in the presence or absence of VLDL. EVs were isolated and labelled with the lipophilic fluorophore PKH67 according to a previously published method [54], and uptake (40 µg ml⁻¹) for 1 h in the absence or presence of VLDL at the indicated concentrations was determined by flow cytometry. *p < 0.05.

Figure 3.

Schematic summary of HSPG-dependent particle uptake in the tumour microenvironment. Lipoproteins and EVs can potentially interact during circulation in the blood and lymph fluid. In the context of the tumour microenvironment, these particles reach tumour resident cells where they can be internalized through an HSPG-mediated mechanism. This process takes place in the cell membrane domains known as lipid rafts and is associated with ERK1/2 activation. HSPG-mediated lipoprotein uptake can induce lipid droplet formation in recipient cells and this may have implications for the tumorigenic potential of these cells. EVs, extracellular vesicles; HSPG, heparan sulphate proteoglycan; LD, lipid droplet; LPR, lipoprotein receptor; SR-B1, scavenger receptor class B member 1; VLDLR, very low density lipoprotein receptor.